The Branch has a long-standing involvement in the systematic evaluation of chemotherapeutic drugs alone or in combination with radiotherapy. As more individuals become long-term cancer survivors, there is greater need to evaluate risk-benefit ratios for various treatment protocols. Branch studies have shown that platinum-based chemotherapy for ovarian cancer was linked to a four-fold risk of leukemia; however, the substantial benefit that platinum-based treatment offers, outweighs the relatively small excess risk of leukemia. A study of leukemia following radiotherapy for testicular cancer revealed a three-fold elevated risk for leukemia, and this risk increased with increasing radiation dose to active bone marrow. The Branch is currently conducting an international cohort study of 32,000 Hodgkin's disease patients to evaluate the risk of radiation and chemotherapy induced second cancers. A study focusing on a subset of 6,000 children and adolescents with Hodgkin's disease indicated a high risk for second cancers of the thyroid and respiratory tract in patients treated before age ten; at older ages, the highest risks were seen for cancers of the digestive tract and breast. An evaluation of new cancers in 28,884 allogeneic BMT recipients demonstrated an increased risk of solid tumors developing among long term survivors. Compared to an age- and sex- matched general population, transplant recipients were at significantly higher 2.3-fold risk of developing new invasive solid cancers. Risk increased with time since transplantation with a nearly 5-fold risk seen among 10 year survivors. The cumulative incidence of invasive second cancers for all patients was 8.1% ? 3.1% at 20 years after transplantation. Sites with significantly increased risk of second cancers were oral cavity, salivary, liver, melanoma, brain, thyroid and bone/connective tissue. While breast cancer risk was not higher than in the general population in early post-transplant time periods, 10-year survivors had a significantly increased risk. A cohort of 1,600 Retinoblastoma(RB) patients continues to be followed to monitor their cancer risk, and RB patients who have developed melanoma are undergoing clinical examination for dysplastic nevi syndrome, lipomas, and mutations in melanoma susceptibility genes. Recent Branch research has demonstrated that children treated for germ-line RB experience a markedly increased risk of lung cancer likely due to somatic mutations of the RB-1 gene are involved in the development of lung cancer. A newsletter informing RB patients of their second cancer risk and preventive measures for smoking cessation was circulated. In collaboration with the Genetic Epidemiology Branch and cancer registries in four Nordic countries, breast cancer risk was reported to be increased in mothers, but not other female relatives, of patients with ataxia-telangiectasia. Expansion of the original cohort and sequencing of the ATM gene in patients and family members is also in progress. A multi-center retrospective cohort study of 5,573 women with scoliosis revealed a statistically significant 1.7-fold risk of death from breast cancer. Patterns were consistent with a radiation etiology in that risk increased with increasing number of diagnostic x-ray examinations and estimated cumulative radiation dose to the breast. Potential confounding between radiation dose and severity of scoliosis may explain some of the excess risk observed. The Branch is currently estimating the risk of cancer after exposure to Thorotrast among several large populations. Thorotrast, once used as an angiographic contrast agent, is not excreted from the body to any appreciable extent; and has induced high rates of liver angiosarcoma and leukemia. The Branch recently completed a 40-year mortality follow-up of 693 Swedish patients with neurological disorders who received Thorotrast. A significant dose-response relation was found for all causes of death combined, and all malignant tumors combined. A second followup study of cancer mortality in a cohort of 2000 irradiated and 2000 surgically treated peptic ulcer patients is in progress. Analyses are focused on increased risks of stomach, pancreatic and lung cancer following radiotherapy in long-term survivors. A retrospective cohort study of cancer mortality in 5,300 subjects treated with nasopharyngeal irradiation (radium) during childhood and 5,200 control subjects in the Netherlands revealed excess deaths due to non-Hodgkin's lymphoma. No excess deaths due to cancers of head and neck were reported. A feasibility of 500 neutron-treated cancer patients did not detect an increased risk of leukemia. Evaluation of chromosome aberrations following neutron exposure demonstrated that neutron-induced dicentrics and rings disappeared within the first three years after exposure, while translocations peristed for more than 17 years. Considerable variability in the number of aberrations between patients who received similar bone marrow doses was noted. A cohort of female tuberculosis patients continues to be studied for the risk of breast cancer following multiple chest fluorscopies received during adolescence and early adult life. Previous studies indicated a dose-response relationship between number of fluorscopies and breast cancer. Preparation of a monograph describing multiple primary cancers in SEER (1973-1998)is underway. The purpose is to clarify the patterns of multiple primary cancers in SEER through a comprehensive evaluation of cancer risk following each initial primary cancer, and to integrate these findings with published literature to further our understanding of cancer etiology. Nested case-control studies of brain, breast and thyroid cancers following an initial childhood cancer are being planned within the large cohort of 5-year childhood cancer survivors. Studies will focus on treatment-induced second cancers. Detailed radiation dosimetry is in progress as well as methodologic work regarding control selection and issues of overmatching. A dosimetry monograph describing methods that have been developed to estimate and reconstruct medical, environmental and occupational radiation exposures in epidemiologic studies conducted by the Branch is in progess. Several studies of thyroid cancer etiology have been conducted. Pooled analyses of 12 international case-control studies of thyroid cancer concluded that goiter and benign nodules/adenomas are the strongest risk factors for thyroid cancer, apart from radiation in childhood. Menstrual and reproductive factors were weakly associated with thyroid cancer, but appeared stronger among women diagnosed at younger ages. A cohort of children irradiated in childhood for enlarged tonsils continues to be followed for the occurrence of thyroid and other head and neck cancers. A study investigating thyroid cancer risk following diagnostic x-rays is comparing medical record data with questionnaire data to evaluate recall bias. Methodologic studies are evaluating dose uncertainty in a study of radiation-induced thyroid cancer in a cohort of Israeli children treated for tinea capitis. The Branch is also evaluating the risk of cancer following diagnostic and therapeutic Iodine-131 in several large, international study populations. Cancer mortality following radiation treatment for benign gynecologic disease in a cohort of 12,000 women is being updated to evaluate solid tumor risk.